Abstract

Pancreatic α-cells express voltage-gated Na+ channels (NaChs) which support the generation of electrical activity leading to increase in intracellular calcium and causes
exocytosis of glucagon. Ranolazine, a NaCh blocker, is approved for treatment for angina. In addition to its anti-anginal
effects, ranolazine has been shown to reduce HbA1c in patients with type 2 diabetes (T2DM) and coronary artery disease; however,
the mechanism behind its anti-diabetic effect has been unclear. We tested the hypothesis that ranolazine exerts its anti-diabetic
effects by inhibiting glucagon release via blockade of NaChs in the pancreatic α-cells. Our data show that ranolazine, via
blockade of NaChs in pancreatic α-cells, inhibits their electrical activity and reduces glucagon release. We found that glucagon
release in human pancreatic islets is mediated by the Nav1.3 isoform. In animal models of diabetes ranolazine and a more selective NaCh blocker (GS-458967) lowered postprandial and
basal glucagon levels, which were associated with a reduction in hyperglycemia, confirming that glucose-lowering effects of
ranolazine are due to blockade of NaChs. This mechanism of action is unique in that no other approved anti-diabetic drugs
act via this mechanism, and raises the prospect that selective Nav1.3 blockers may constitute a novel approach for the treatment of diabetes.

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